TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613-620.] septic shock [Mathison, et. a.l J. Clin. Invest. 1988, 81, 1925; Miethke, et. al. J. Exp. Med. 1992, 175, 91.], graft rejection [Piguet, P. F.; Grau, G. E.; et. al. J. Exp. Med. 1987, 166, 1280.], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505-518.], anorexia, inflammation [Ksontini, R.; MacKay, S. L. D.; Moldawer, L. L. Arch. Surg. 1998, 133, 558-567.], congestive heart failure [Packer, M. Circulation, 1995, 92(6), 1379; Pages 1-8; Ferrari, R.; Bachetti, T.; et. al. Circulation, 1995, 92(6), 1479, 1-12.], post-ischaemic reperfusion injury, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M.; et. al. Science, 1993, 259, 87-91.] and HIV infection [Peterson, P. K.; Gekker, G.; et. al. J. Clin. Invest 1992, 89, 574-580; Pallares-Trujillo, J.; Lopez-Soriano, F. J. Argiles, J. M. Med. Res. Reviews, 1995, 15(6), 533-546.]], in addition to its well-documented antitumor properties [Old, L. Science, 1985, 230, 630-632.]. For example, research with anti-TNF-α antibodies and transgenic animals has demonstrated that blocking the formation of TNF-α inhibits the progression of arthritis [Rankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A. M.; Isenberg, D. A.; Panayi, G. S. Br. J. Rheumatol. 1995, 34, 334-342; Pharmaprojects, 1996, Therapeutic Updates 17 (October), au197-M2Z.]. This observation has recently been extended to humans as well as described in “TNF-α in Human Diseases”, Current Pharmaceutical Design, 1996, 2, 662-667.
It is expected that small molecule inhibitors of TACE would have the potential for treating a variety of disease states [Nelson, F. C.; Zask, A. Exp. Opin. Invest. Drugs 1999, 8, 383-392; Lowe, C. Exp. Opin. Ther. Patents 1998, 8, 1309-1322; Newton, R. C.; Decicco, C. P. J. Med. Chem. 1999, 42, 22952314.]. Although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like [Cherney, R. J.; Wang, L.; Meyer, D. T.; et. al. Bioorg. Med. Chem. Lett., 1999, 9, 1279-1284; Xue, C.-B.; He, X.; Roderick, J. J. Med. Chem., 1998, 41, 1745-1748; Barlaam, B.; Bird, T. G.; Lambert-van der Brempt, C.; et. al. J. Med. Chem., 1999, 42, 4890-4902; Xue, C.-B.; Voss, M. E.; Nelson, D. J.; et. al. J. Med. Chem., 2001, 44, 2636-2660; Kottirsch, G; et al. J. Med. Chem. 2002, 45, 2289-2293; Rabinowitz, M. H.; et al. J. Med. Chem. 2001, 44, 4252-4267; Beck, G.; et al. J. Pharmacol. Exp. Ther. 2002, 302, 390-396; WIPO international publications WO0032570, WO0035885, WO9918074, WO0059285] which suffer from bioavailability and pharmacokinetic problems. In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20]. A lactam hydroxamic acid TACE inhibitor that is selective over many MMPs has been reported [Duan, J. J.-W.; et al. J. Med. Chem. 2002, 45, 4954-4957.]. Long-acting, selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above.
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc-containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, scirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection. For recent reviews, see: Michaelides, M. R.; Curtin, M. L. Curr. Pharm. Design 1999, 5, 787-819 and Skiles, J. W.; Gonnella, N. C.; Jeng, A. Y. Curr. Med. Chem. 2001, 8, 425-474.
Examples of sulfonamide hydroxamic acid MMP/TACE inhibitors in which a 2-carbon chain separates the hydroxamic acid and the sulfonamide nitrogen, as shown below, are disclosed in WIPO international publications WO9816503, WO9816506, WO9816514 and WO9816520 and U.S. Pat. Nos. 5,929,097, 5,962,481, 5,977,408 6,162,814, 6,162821, 6,197,795, and 6,228,869. These compounds are further detailed by Levin, et al. in Bioorg. Med. Chem. Lett. 2001, 11, 235-238; Bioorg. Med. Chem. Lett. 2001, 11, 239-242; Bioorg. Med. Chem. Lett. 2001, 11, 2189-2192; Bioorg. Med. Chem. Lett. 2001, 11, 2975-2978.

Examples of sulfonamide hydroxamic acid MMP/TACE inhibitors bearing an acetylenic substituent, are disclosed in WIPO international publications WO9839315, WO0044713, WO0044749, WO0044740, WO0044730, WO0044711, WO0044716, WO0044710, WO0044709, WO0044723, U.S. Pat. Nos. 6,200,996, 6,326,516, 6,277,885, 6,228,869, 6,225,311, 6,313,123, Chen et al. in Bioorg. Med. Chem. Lett. 2002, 12, 1195-1198 and Levin, et al. in Bioorg. Med. Chem. Lett. 2002, 12, 1199-1202.
U.S. Pat. Nos. 5,455,258, 5,506,242, 5,552,419, 5,770,624, 5,804,593 and 5,817,822 as well as European patent application EP606,046-A-1 and WIPO international publications WO9600214 and WO9722587 disclose non-peptide inhibitors of matrix metalloproteinases and/or TACE of which the aryl sulfonamide hydroxamic acid shown below, in which 1 carbon separates the hydroxamic acid and the sulfonamide nitrogen, is representative. Additional publications disclosing sulfonamide based MMP/TACE inhibitors which are variants of the sulfonamide-hydroxamate shown below, or the analogous sulfonamide-carboxylates, are European patent applications EP-757037-A1 and EP-757984-A1 and WIPO international publications WO9535275, WO9535276, WO9627583, WO9719068, WO9727174, WO9745402, WO9807697, and WO9831664, WO9833768, WO9839313, WO9839329, WO9842659, WO9843963, WO0110827, WO0127084. The discovery of this type of MMP/TACE inhibitor is further detailed by MacPherson, et. al. in J. Med. Chem., (1997), 40, 2525-2532, Tamura, et al. in J. Med. Chem. (1998), 41, 640-649, Letavic, M. A.; et al. in Bioorg. Med. Chem. Lett. 2002, 12, 1387-1390, and Holms, J. et al. in Bioorg. Med. Chem. Lett. 2001, 11, 2907-2910.

Publications disclosing α-sulfonamide-hydroxamate inhibitors of MMPs and/or TACE in which the carbon alpha to the hydroxamic acid has been joined in a ring to the sulfonamide nitrogen, as shown below, include U.S. Pat. No. 5,753,653, WIPO international publications WO9633172, WO9720824, WO9827069, WO9808815, WO9808822, WO9808823, WO9808825, WO9834918, WO9808827, WO0009492, Levin, et. al. Bioorg. & Med. Chem. Letters 1998, 8, 2657-2662 and Pikul, et. al. J. Med. Chem. 1998, 41, 3568-3571.

The patent applications DE19,542,189-A1, WO9718194, and EP803505 disclose additional examples of cyclic sulfonamides as MMP and/or TACE inhibitors. In this case the sulfonamide-containing ring is fused to an aromatic or heteroaromatic ring.

Analogous to the sulfonamides are the phosphinic acid amide hydroxamic acid MMP/TACE inhibitors, exemplified by the structure below, which have been disclosed in WIPO international publication WO9808853.

Sulfonamide MMP/TACE inhibitors in which a thiol is the zinc chelating group, as shown below, have been disclosed in WIPO international application 9803166 and U.S. Pat. No. 6,313,123.

It is an object of this invention to disclose aryl sulfonate hydroxamic acid TACE inhibitors and MMP inhibitors in which the sulfonyl aryl group is para-substituted with a substituted butynyl moiety or a propargylic ether, amine or sulfide. These compounds inhibit the activity of TACE in vitro, and provide selectivity over MMP-1 and MMP-13. These compounds may therefore be used in the treatment of diseases mediated by TNF.